Urotropine Isomer (1,4,6,10-Tetraazaadamantane): Synthesis

Jun 9, 2014 - The first synthesis of 1,4,6,10-tetraazaadamantane, the C3v-symmetrical structural isomer of urotropine (1,3,5,7-tetraazaadamantane), an...
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Urotropine Isomer (1,4,6,10-Tetraazaadamantane): Synthesis, Structure, and Chemistry Artem N. Semakin,† Alexey Yu. Sukhorukov,*,† Yulia V. Nelyubina,‡ Yulia A. Khomutova,† Sema L. Ioffe,† and Vladimir A. Tartakovsky† †

N.D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991, Moscow, Russia A.N. Nesmeyanov Institute of Organoelement Compounds, Vavilov str. 28, 119991, Moscow, Russia

‡

S Supporting Information *

ABSTRACT: The first synthesis of 1,4,6,10-tetraazaadamantane, the C3vsymmetrical structural isomer of urotropine (1,3,5,7-tetraazaadamantane), and a series of its derivatives is reported. X-ray and quantum-chemical studies revealed remarkable distinctions in structures of urotropine and “isourotropine” cations, probably arising from different types of hyperconjugation between lone electron pairs of nitrogen atoms and σ*C−N orbitals in these heterocage systems. Since substitution at bridge and bridgehead nitrogen atoms can be easily introduced, 1,4,6,10-tetraazaadamantane may be considered as a new rigid multivalent (3 + 1) scaffold for the design of functional molecules and materials.

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INTRODUCTION For more than 100 years, heteroadamantanes have been objects of vast attention from fundamental and applied chemistry. These cage polycyclic systems represent interest not only due to their unique properties,1 but also as convenient models for the study of basic problems dealing with structure and reactivity of organic compounds.2 Among many heteroadamantanes, 1,3,5,7-tetraazaadamantane (urotropine), which was first obtained by A. Butlerow in 1859, plays, probably, the most important role from an applied point of view.3 Urotropine is used as a drug to treat bacterial infections,4a,b equivalent of formaldehyde in polymer production,4a,c intermediate in synthesis of high energy materials,4d food additive,4e as well as a valuable reagent in organic synthesis4f and ligand in coordination chemistry.4g Until recently urotropine was the only known representative of the class of tetraazaadamantanes (Figure 1).5 In this context the possibility of existence of other tetraazaadamantanes isomeric to urotropine represents considerable fundamental interest (Figure 1). According to quantumchemical calculations at G3(MP2) level of theory urotropine (ΔH°f,298(exp) = 47.5 kcal/mol, ΔH°f,298(G3(MP2)) = 49.3 kcal/mol6) is the least thermodynamically stable of the four possible isomeric tetraazaadamantanes possessing no nitrogen− nitrogen bonds (Figure 1).7 These results predict the stability of tetraazaadamantanes isomeric to urotropine or, for instance, some of their derivatives. From the diversity-oriented molecular design standpoint the C3v-symmetrical urotropine isomer, 1,4,6,10-tetraazaadamantane 1a (Figure 1), is of special concern. Because of the presence of three bridge and one bridgehead nitrogen atoms, which can be modified employing reactions with electrophilic agents, molecule 1a can be considered as a universal multivalent (3 + 1) scaffold for the construction of various functional © 2014 American Chemical Society

Figure 1. Urotropine and isomeric tetraazaadamantanes possessing no N−N bonds.

molecules and materials (bioconjugates, systems for molecular recognition and drug delivery, dendrimers, high energy materials).8 1,4,6,10-Tetraazaadamantane cage may serve as a rigid three-dimensional matrix providing tripodal arrangement of functional fragments E1 with an orthogonal group E2 (Figure 2). Substitution at bridgehead carbon atoms provides additional opportunities for the introduction of functional fragments (substituents R, Figure 2). In contrast to 1a, urotropine cannot be used as a multivalent scaffold, since its derivatives possessing substituents at more then two nitrogen atoms are unstable.9a,b Received: April 4, 2014 Published: June 9, 2014 6079

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Scheme 2. Synthesis of 1,4,6,10-Tetraazaadamantane 1a

adamantanes are associated with larger steric hindrance of substituted hydroxylamine fragments. It is noteworthy, that increasing of temperature in reduction of 3b and 3c results in tetraazaadaamantane cage opening to give corresponding trisoximes 2b and 2c.5 Product 1a is the first member of 1,4,6,10-tetraazaadamantane family and the only up-to-date obtained structural isomer of urotropine. Unlike urotropine, “isourotropine” 1a proved to be quite a labile compound, which easily underwent oligomerization at room temperature. It is likely that the instability of 1a is associated with adamantane opening and subsequent polymerization of highly reactive imine groups. The lability and tendency toward polymerization are typical for some other heterocage compounds possessing N−H aminal fragments.1c,12 Previously we demonstrated that quaternization of bridgehead nitrogen in 4,6,10-trihydroxy-1,4,6,10-tetraazaadamantanes 3 to give N-benzyl salts 4 (R2 = Bn, Scheme 1) results in remarkable stabilization of adamantane cage with respect to acyclic tris-oxime form.5 We speculated that such a stabilization may also take place in case of 1,4,6,10-tetraazaadamantanes 1 unsubstituted at nitrogen atoms. To validate this hypothesis we studied the reduction of trihydroxytetraazaadamantane Nbenzyl salt 4a (Scheme 3, Table 1). Several different

Figure 2. 1,4,6,10-Tetraazaadamantane as multivalent (3 + 1) scaffold.

In the present work, the synthesis of 1,4,6,10-tetraazaadamantane 1a and a series of its C- and N-substituted derivatives was realized as well as their structure and reactivity were studied.

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RESULTS AND DISCUSSION Synthesis of 1,4,6,10-Tetraazaadamantanes. In our preliminarily communication5 we reported the synthesis of Nhydroxy-substituted 1,4,6,10-tetraazaadamantanes 3 and their salts 4 employing an unprecedented intramolecular cyclotrimerization of oxime groups in tris(β-oximinoalkyl)amines 2 (Scheme 1). Using this simple approach a series of adamantanes 3a−c and 4a−e were prepared. Scheme 1. Cyclotrimerization of Tris-Oximes 2 to 1,4,6,10Tetraazaadamantane Derivatives 3 and 4

Scheme 3. Synthesis of 1,4,6,10-Tetraazaadamantanes 1a−c

For the synthesis of 1,4,6,10-tetraazaadamantanes 1 unsubstitituted at nitrogen atoms selective reduction of N-hydroxy fragments in products 3 or their salts 4 is required without aminal groups being affected. Hydrogenolysis of N−O bond in the presence of labile aminal fragment is quite challenging and has very few precedents in literature.10 First, we investigated the interaction of trihydroxytetraazaadamantane 3a (Scheme 1, R1 = H) with a series of classical agents employed previously for the reduction of N,Ndialkylhydroxylamine fragment (LiAlH4, Zn dust, Al/Hg and catalytic hydrogenation).11 Typically, either no conversion of starting material was observed or indecipherable product mixtures were obtained. Fortunately, upon catalytic hydrogenation in the presence of Raney nickel at room temperature initial adamantane 3a was rapidly converted (25−30 min) into target product 1a in high yield (Scheme 2). However, this procedure could not be extended to substituted trihydroxyadamantanes 3b and 3c (Scheme 1, R1 = CH3, Bn). Probably, difficulties in the reduction of these

mechanism-based types of reducing agents were examined (H2/Raney Ni or Pd/C,11a,b Mo(CO)6/H2O,11c Al/Hg,11a Na/ Hg,11a Zn/NH4Cl11d). In most of cases, except for the reduction with zinc, either starting material, or complex Table 1. Reduction of Tetraazaadamantanes 4a−e 4→5

6080

1

entry

4

R

1 2 3 4 5

4a 4b 4c 4d 4e

H CH3 Bn H CH3

R

2

Bn Bn Bn CH3 CH3

5→1

X

time, h

yield, %

yield, %

Br Br Br I I

15 6 15 8 10

82 90 76 90 92

88 80 67 − −

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In crystal of 5a·CH3OH N−H fragments form from weak to very weak hydrogen bonds with bromine anions; the corresponding distances N···Br vary from 3.4422(19) to 3.767(1) Å. Comparison of the structures of N-benzyl 1,4,6,10tetraazaadamantanium cation (5a) and isomeric N-benzyl 1,3,5,7-tetraazaadamantanium cation 5a′ (for X-ray see ref 16) warrants special discussion (Figure 4). An intriguing feature

mixtures of products were obtained. Zinc dust in water or methanol upon ultrasonic activation was found to be the reagent of choice for the reduction of N-benzyl adamantane 4a to give products 5a.13 It is likely that the role of untrasound activation consists in depassivation of zinc particles by removing from their surface zinc hydroxide layer forming upon the reduction process (Scheme 3).14 With these reduction conditions in hand a series of N-methyl and N-benzyl quaternary salts of 1,4,6,10-tetraazaadamantanes 5a−e unsubstituted at bridge nitrogen atoms were synthesized (Scheme 3, Table 1). All these tetraazaadamantanes are thermally stable and undergo decomposition only upon melting at temperatures around 130−220 °C. Mild hydrogenolysis of benzylic C−N bond15 in 5a-c furnished free N−H adamantanes 1a−c (Scheme 3). Tetraazaadamantanes 1b and 1c proved to be more stable than the unsubstituted “isourotropine” 1a. On the contrary, the presence of substituents at carbon atoms of urotropine cage destabilizes its structure.9c Structure of 1,4,6,10-Tetraazaadaamantanes. The identity and purity of tetraazaaadamantanes 1a−c and 5a−e were confirmed by 1H and 13C NMR, elemental analysis and high-resolution mass-spectrometry data. The structure of adamantane 5a was established by X-ray crystallography (CCDC 966626, crystal solvate with methanol). The cation of 5a is a nearly C3v symmetrical tetraazaadamantane (Figure 3). Carbon−nitrogen bonds in 1,3,5-triazine

Figure 4. Anomeric effects in cations 5a and 5a′.

of cation 5a is flattening of the triazine cycle as compared to urotropinium cation 5a′. This is illustrated by smaller deviations of bridge atoms (N(1), N(2) and N(3)) from the mean plane of three bridgehead atoms (C(1)C(1′)C(1″)) in cation 5a. Furthermore, bond angles N−C−N in triazine cycle of 5a are larger than in cation 5a′ and considerably deviate from tetrahedral angles (cf. data in Table 2). Another interesting feature of 1,4,6,10-tetraazaadamantane cage of 5a is the shortening of C−N bonds between quaternary nitrogen atom N(4) and carbon atoms C(2), C(2′) and C(2″) as compared to 1,3,5,7-tetraazaadamantane 5a′. On the other hand, C−N bonds in triazine cycle (C(1)N(1)C(1′)N(3)C(1″)N(2)) of 5a and 5a′ have virtually the same length (cf. data in Table 2). We reasoned that the observed distinctions in 1,4,6,10- and 1,3,5,7-tetraazaadamantanes structures result from different stereoelectronic interactions involving nitrogen atoms N(1), N(2), N(3) and N(4) in these two molecules (Table 2, Figure 4). Thus, in 1,3,5,7-tetraazaadamantane cage of 5a′ lone electron pairs of nitrogen atoms may interact with antibonding orbitals of six C−N bonds in triazine cycle (lp(Neq) → σ*C−N donation) as well as with antibonding orbitals of three C− N(4)+ bonds (lp(Neq) → σ*C−N+ donation, Figure 4). In 1,4,6,10-tetraazaadamantane cation (5a) only one type of such anomeric interactions (lp(Neq) → σ*C−N donation) involving nitrogen atoms is possible (Figure 4). To estimate the energies of these interactions natural bold orbital analysis (NBO) was performed for cations 5a and 5a′. As can be seen from data in Table 2 theoretical models of 1,4,6,10- and 1,3,5,7-tetraazaadamantanium cations developed by quantum-chemical calculations at G3MP2 level of theory are in good agreement with Xray data. According to NBO analysis the energy of lp(Neq) → σ*C−N hyperconjugation in 1,4,6,10-tetraazaadamantanium cation is 2.5 kcal/mol greater than in 1,3,5,7-tetraazaadamantanium cation. The occupancies of C−N antibonding orbitals in 5a and 5a′ are 0.045 and 0.039 electrons, respectively. Accordingly, nitrogens lone electron pairs interact more efficiently with C−N antibonding orbitals in 1,4,6,10tetraazaadamantanium cation than in urotropinium cation. Apparently, this is due to an additional hyperconjugation of nitrogens lone pairs with antibonding C−N(4)+ orbitals (lp(Neq) → σ*C−N+) in urotropinium salt 5a′, which results in experimentally observed elongation of C(2)−N(4)+, C(2′)− N(4)+ and C(2″)−N(4)+ bonds (Table 2). Decrease of the

Figure 3. General view of the cation in a crystal 5a·CH3OH in representation of atoms via thermal ellipsoids (p = 50%).

ring fall in a narrow range of 1.469(2)−1.472(2) Å and thus are virtually equalized. In the same way, C−N bonds incorporating N(4) atom, as well as C−C bonds in 5a, have very similar lengths (1.508(2)−1.517(2) Å and 1.517(3)−1.523(3) Å, respectively). N−H fragments in triazine ring of 1,4,6,10-tetraazaadamantane cation 5a are located in axial positions. This is in agreement with G3(MP2) calculations on four 1,4,6,10tetraazaadamantane invertomers, which predict the all N−H axial isomer to be the most thermodynamically favored. The all N−H equatorial isomer is the least stable (ΔH = +11 kcal/mol as compared to all N−H axial isomer), probably due to the presence of three destabilizing 1,3-diaxial lone pair-lone pair interactions (cf. data in Table S1 in Supporting Information). 6081

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Table 2. Experimental (X-ray) and Calculated Characteristic Structural and Energetic Parameters of N-Benzyl 1,4,6,10Tetraazaadamantanium (5a) and N-Benzyl 1,3,5,7-Tetraazaadamantanium Cations (5a′) 4-benzyl 1,4,6,10-tetraazaadamantanium cation (5a) parameter +

C−N , Å C(2)−N(4), C(2′)−N(4) C(2″)−N(4) C−N, Å C(1)−N(1), C(1′)−N(1) C(1)−N(2), C(1″)−N(2), C(1′)−N(3), C(1″)−N(3) ∠N−C−N, deg ∠N(1)−C(1)−N(2) ∠N(1)−C(1′)−N(3), ∠N(2)−C(1″)−N(3) deviationb, Å lp(Neq) → σ*C−N, kcal/mol lp(Neq) → σ*C−N+, kcal/mol

theorya

experiment

1-benzyl 1,3,5,7-tetraazaadamantanium cation (5a′) experiment16

theorya

1.508(2)−1.517(2)

1.508−1.510

1.523(5)−1.550(4)

1.527

1.469(2)−1.472(2)

1.463−1.464

1.467(5)−1.484(5)

1.460−1.461

114.36(15)−115.06(15)

115.91−116.05

110.6(3)−111.7(3)

110.09−110.12

0.43(1)−0.44(1) − −

0.41−0.42 10.7−10.8 −

0.47−0.49 − −

0.48 8.3−8.4 14.4−14.5

a Ab initio G3(MP2) method was used for geometry optimization, B3LYP/6-311+G** basis set for NBO analysis. bDeviation of bridge atoms (nitrogen in case of 5a and carbon in case of 5a′) from the mean plane created by three bridgehead atoms (C(1)C(2)C(3) in 5a and N(1)N(2)N(3) in 5a′) in triazine cycle.

Scheme 4. Modifications of 1,4,6,10-Tetraazaadaamantane N-Benzyl salt 5a

Unexpectedly, reaction of benzyl salt 5a with di(tertbutyl)dicarbonate (Boc2O) resulted in the selective introduction of one Boc-group providing adamantane 8a in 95% yield. The absence of products of double and triple addition is probably caused by steric hindrance created by the first Bocgroup attached to adamantane skeleton. This result allows to differentiate bridge nitrogen atoms in 5a and thus to synthesize unsymmetrically substituted 1,4,6,10tetraazaadamantanes. In particular, double acetylation of 8a with acetic anhydride gave the unsymmetrically substituted adamantane 9a (Scheme 4). Catalytic reductive debenzylation of 8a and 9a with hydrogen over Pd/C furnished free tertiary bases 10a and 11a, respectively. Alkylation of adamantane 5a was studied employing reactive alkyl halides (methyl iodide and benzyl bromide in the presence of potassium carbonate as a base) and Michael acceptors such as methyl acrylate, acrylonitrile and methyl vinyl ketone. However, no conversion of initial adamantane 5a was observed in reaction with alkyl halides. Similarly, no reaction was detected between 5a and acrylonitrile. Interaction of methyl

pyramidality of bridge nitrogen atoms N(1), N(2) and N(3) should account for the observed flattening of the triazine cycle and increasing of N−C−N bond angles in cation 5a as compared to 5a′.17 Thus, key differences in structures of 1,4,6,10- and 1,3,5,7-tetraazaadamantanes are governed by stereoelectronic reasons. Modifications of 1,4,6,10-Tetraazaadaamantanes. The presence of three secondary amino groups in combination with thermal stability and the relative ease of reductive debenzylation make quaternary N-benzyl salts 5 perspective precursors of various 1,4,6,10-tetraazaadamantanes functionalized at bridge nitrogen atoms. To demonstrate these possibilities, reactions of salt 5a with different electrophilic (acetylating, alkylating and nitrosylating) agents were studied (Scheme 4). Thus, treatment of adamantane 5a with an excess of acetic anhydride in acetic acid led to the acylation of all three secondary amino groups forming triacetyl derivative 6a in high yield (Scheme 4). Subsequent reductive debenzylation of product 6a furnished the desired N,N,N-triacetyl-1,4,6,10tetraazaadamantane 7a in good yield. 6082

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in round-bottom Schlenk-type flasks equipped with magnetic stirring bar using rubber balloon with hydrogen. In NMR spectra residual solvents peaks were used as an internal standard. Half-height widths of peaks (W in Hz) are reported for broad C−H signals. HRMS spectra were recorded on a mass spectrometer with electrospray ionization and TOF mass analyzer. Melting points (uncorrected) were determined on a hot-stage microscope. Commercial reagents were used without additional purification. Tris-oximes 2a−c,19 4,6,10trihydroxy-1,4,6,10-tetraazaadamantanes 3a−c5 and their N-benzyl salts 4a−c5 were prepared according to our previously reported procedures. Synthesis of N-Methyl Quaternary Salts 4d,e. Acetic acid (860 μL, 15.0 mmol) and MeI (375 μL, 6.0 mmol) were added to a solution of tris-oxime 2a,b (5.0 mmol) in MeOH (15 mL). The reaction mixture was kept overnight and volatile components were evaporated. The white solid residue was triturated with EtOAc−MeOH (3:1) and dried in a vacuum (0.25 Torr) until constant weight. 4,6,10-Trihydroxy-1-methyl-1,4,6,10-tetraazaadamantan-1-ium iodide (4d). 1.53 g (yield 93%). White crystals: mp 204−206 °C (with dec.); 1H NMR (300 MHz, DMSO-d6) δ = 3.12 (s, 3 H), 3.72 (br s, W = 40 Hz, 6 H), 4.29 (s, 3 H), 8.8−9.3 (br, 3 H); 13C NMR (75 MHz, DMSO-d6) δ = 52.1, 53−57 (br, W = 165 Hz), 71−75 (br, W = 180 Hz); ESI-HRMS m/z [M − I]+ Calcd for C7H15N4O3 m/z 203.1139, found 203.1137. 1,3,5,7-Tetramethyl-4,6,10-trihydroxy-1,4,6,10-tetraazaadamantan-1-ium iodide (4e). 1.80 g (yield 97%). White crystals: mp 193− 199 °C (with dec.); 1H NMR (300 MHz, DMSO-d6) δ = 1.22 (s, 9 H), 3.05 (s, 3 H), 3.42 (br, W = 17 Hz, 6 H), 8.1−8.7 (br, 3 H); 13C NMR (75 MHz, DMSO-d6) δ = 19.4, 52.8, 55−60 (br, W = 110 Hz), 74−77 (br, W = 55 Hz); ESI-HRMS m/z [M − I]+ Calcd for C10H21N4O3 m/z 245.1608, found 245.1609. Synthesis of 1,4,6,10-Tetraazaadamantane (1a). A suspension of Raney Nickel in MeOH (ca. 50 mg Ni) was added to a solution of 4,6,10-trihydroxy-1,4,6,10-tetraazaadamantane 3a (50 mg, 0.26 mmol) in MeOH (2.5 mL) the under argon atmosphere. The reaction vessel was evacuated and filled with hydrogen three times. Hydrogenation was performed at 1 atm H2 until full conversion of 3a (45−60 min, TLC control). Then the catalyst was separated by centrifugation, and the reaction mixture was evaporated at 40 Torr and 35 °C and then dried in a vacuum (0.25 Torr) until constant weight. 1,4,6,10Tetraazaadamantane 1a was obtained as a white foam (33 mg, yield 90%): 1H NMR (300 MHz, DMSO-d6) δ = 2.45 (s, 3 H), 3.17 (s, 6 H), 3.62 (s, 3 H); 13C NMR (75 MHz, DEPT, DMSO-d6) δ = 57.1 (CH2), 61.5 (CH); ESI-HRMS m/z [M + H]+ Calcd for C6H13N4 141.1135, found 141.1132. Synthesis of 1,4,6,10-Tetraazaadamantan-1-ium Salts 5a−e. Zinc dust (10 g, 153 mmol) was added to a solution of 4,6,10trihydroxy-1,4,6,10-tetraazaadamantanium salts 4a-e (5 mmol) in distilled water (15 mL) under argon atmosphere. The reaction vessel was placed in ultrasonic cleaner and kept under ultrasonic irradiation (37 kHz, 150 W) at 80−85 °C until full consumption of starting material (NMR monitoring, 6−15 h, Table 1). The inorganic precipitate was centrifuged off and washed with MeOH. Combined solutions were evaporated in a vacuum (40 Torr) at 50−55 °C. The residue was triturated with EtOAc or EtOAc−MeOH mixture (5:1) and dried in vacuo (0.25 Torr) and then in a desiccator (P2O5) until constant weight. 1-Benzyl-1,4,6,10-tetraazaadamantan-1-ium bromide (5a). 1.27 g (yield 82%). White solid: mp 220−222 °C (with dec.); 1H NMR (300 MHz, DMSO-d6) δ = 3.04 (s, 3 H), 3.63 (s, 6 H), 4.23 (s, 3 H,), 4.66 (s, 2 H), 7.50−7.61 (s, 5 H); 13C NMR (75 MHz, DEPT, DMSO-d6) δ = 59.5 (CH), 61.3 (CH2), 68.1 (CH2), 126.3 (C), 128.8 (CH), 130.3 (CH), 133.0 (CH); ESI-HRMS m/z [M − Br]+ Calcd for C13H19N4 231.1604, found 231.1601. Anal. Calcd for C13H19BrN4: C, 50.17; H, 6.15; N, 18.00. Found: C, 50.11; H, 6.35; N, 18.22. 1-Benzyl-3,5,7-trimethyl-1,4,6,10-tetraazaadamantan-1-ium bromide (5b). 1.59 g (yield 90%). White solid: mp 193−205 °C (with dec.); 1H NMR (300 MHz, DMSO-d6) δ = 1.09 (s, 9 H), 2.41 (s, 3 H), 3.21 (s, 6 H), 4.61 (s, 2 H), 7.51−7.60 (m, 5 H); 13C NMR (75 MHz, DEPT, DMSO-d6) δ = 25.3 (CH3), 62.9 (CH2) and 63.6

acrylate with adamantane 5a furnished an inseparable mixture of starting material and monoalkylation product (ratio ca. 5:3 according to 1H NMR data). Full conversion of 5a could not be reached neither with a large excess of methyl acrylate nor under prolongated reflux time. On the contrary, reaction of 5a with an excess of methyl vinyl ketone in methanol led to a smooth formation of the tris-adduct 12a (Scheme 4). The later was transformed into tertiary base 13a by catalytic hydrogenation over Pd/C in the presence of potassium carbonate (Scheme 4). Nitrosylation is a typical reaction of secondary amines leading to N-nitrosoamines. Accordingly, treatment of benzyl salt 5a with an excess of tert-butyl nitrite furnished a N,N,Ntris(nitroso)adamantane 14a in high yield. Interestingly, in the course of nitrosylation bromine anion was substituted for a nitrate. This may result from the action of nitric acid formed by oxidation of nitrogen oxides exposed from the excess of nitrosylation agent (examples of such oxidative bromine anion substitution for nitrate anion with nitric acids are precedent in literature18). However, attempts to react the trimethyl substituted adamantane 5b (R1 = CH3, R2 = Bn, Table 1) with electrophilic agents failed. No reaction was observed with acetic anhydride and Boc2O; interaction of 5b with methyl vinyl ketone or tertbutyl nitrite furnished complex mixtures of unidentified products. It is likely that the lack of reactivity of adamantane 5b is associated with a greater sterical hindrance of secondary amino groups in its structure. Thus, N-benzyl salt 5a may be considered as a stable equivalent of “isourotropine” in the construction of functional molecules based on 1,4,6,10-tetraazaadamantane scaffold.

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CONCLUSIONS Though much research was done in 1960−1990s, the chemistry and structure of heteroadamantanes still remains a matter of considerable scientific interest.2a−h In this work, 1,4,6,10tetraazaadamantane, the structural isomer of urotropine, and a series of its derivatives substituted at carbon and nitrogen atoms have been synthesized for the first time. The suggested strategy utilizes available aliphatic nitro compounds as starting materials and involves an unusual intramolecular cyclotrimerization of oxime groups in tris-oximes 2, reduction of N−OH fragments in the resulting adamantanes 3 or 4 and subsequent electrophilic addition to bridge nitrogen atoms. 1,4,6,10-Tetraazaadamantane structure demonstrates marked distinctions from the urotropine cage, which are governed by strong lp(Neq) → σ*C−N hyperconjugation. Furthermore, Cand N-polysubstituted 1,4,6,10-tetraazaadamantanes proved to be more stable than the substituted urotropine derivatives. This implies that the chemical space of 1,4,6,10-tetraazaadamantanes is much greater than that of 1,3,5,7-tetraazaadamantanes. As is demonstrated here, N-benzyl salt 5a may serve as a universal and stable building-block for the molecular design of various 1,4,6,10-tetraazaadamantane derivatives possessing antiperiplanar or orthogonal oriented functional fragments. Because of the approach suggested by us, the class of 1,4,6,10tetraazaadamantanes can be considered as available now.

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EXPERIMENTAL SECTION

All reactions were performed in oven-dried (125 C) glass-ware. Reactions were monitored by analytical TLC using silica gel TLC plates with QF-254. Visualization was accomplished with UV light and the solution of ninhydrin in methanol. Methanol for reactions was distilled without drying agents. Catalytic hydrogenation was performed 6083

dx.doi.org/10.1021/jo5007703 | J. Org. Chem. 2014, 79, 6079−6086

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major rotamers), 58.7, 59.6, 60.3, 67.8, 80.3, 126.0, 128.9, 130.5 and 133.1, 152.7; ESI-HRMS m/z [M − Br]+ Calcd for C18H27N4O2 331.2129, found 331.2131. Anal. Calcd for C18H27N4O2Br: C, 52.56; H, 6.62; N, 13.62. Found: C, 52.74; H, 6.89; N, 13.53. Synthesis of 4,6-Diacetyl-1-benzyl-10-[(tert-butoxy)carbonyl]-1,4,6,10-tetraazaadamantan-1-ium bromide (9a). Ac2O (170 μL, 1.80 mmol) was added to a solution of 8a (50 mg, 0.12 mmol) in AcOH (2 mL). The reaction mixture was stirred for 12 h, and volatile components were evaporated. The residue was triturated with EtOAc−MeOH (10:1) and dried in a vacuum (0.25 Torr) until constant weight (49 mg, yield 83%). White solid: mp 168− 175 °C; 1H NMR (300 MHz, mixture of rotamers, DMSO-d6) δ = 1.41 (s, 9 H), 2.14 (s, 6 H), 3.85 and 3.97 (2 br m, W = 30 and 19 Hz, 6 H), 4.76 (s, 2 H), 6.40 and 6.61 (2 br m, W = 35 and 50 Hz, 2 and 1 H), 7.45−7.66 (m, 5 H); 13C NMR (75 MHz, DMSO-d6) δ = 20.2, 27.5, 55.3 (br, W = 50 Hz), 58.3 (br, W = 45 Hz), 58.7 (br, W = 10 Hz), 59.7 (br, W = 30 Hz), 67.7, 82.2, 125.5, 129.0, 130.6, 133.0, 151.6, 166.3; ESI-HRMS m/z [M − Br]+ Calcd for C22H31N4O4 415.2340, found 415.2317. Synthesis of 1-Benzyl-4,6,10-tris(3-oxobuthyl)-1,4,6,10-tetraazaadamantan-1-ium bromide (12a). Methyl vinyl ketone (800 μL, 9.6 mmol) was added to a solution of 5a (100 mg, 0.32 mmol) in MeOH (5 mL). The reaction mixture was kept for 12 h, and volatile components were evaporated. The residue was washed with Et2O and dried in a vacuum (0.25 Torr) until constant weight (165 mg, yield 99%). White solid: mp 185−192 °C (with dec.); 1H NMR (300 MHz, DMSO-d6) δ = 2.07 (s, 9 H), 2.53 (t, J = 6.4 Hz, 6 H), 2.93 (t, J = 6.4 Hz, 6 H), 3.45 (s, 6 H), 3.96 (s, 3 H), 4.60 (s, 2 H), 7.53 (s, 5 H); 13C NMR (75 MHz, DEPT, DMSO-d6) δ = 29.8 (CH3), 42.0 (CH2), 46.1 (CH2), 56.4 (CH2), 67.0 (CH), 67.8 (CH2), 126.1 (C), 129.0 (CH), 130.5 (CH), 133.0 (CH), 207.7 (C); ESI-HRMS m/z [M − Br]+ Calcd for C25H37N4O3 441.2860, found 441.2858. Synthesis of 1-Benzyl-4,6,10-trinitrozo-1,4,6,10-tetraazaadamantan-1-ium nitrate (14a). Tert-BuONO (420 μL, 3.6 mmol) was added to a solution of 5a (75 mg, 0.24 mmol) in AcOH (2 mL) at ∼10 °C, and reaction mixture was kept at 0 °C for 12 h. Volatile components were evaporated, and the residue was triturated with EtOAc−MeOH (10:1) and dried in vacuo (0.25 Torr) until constant weight (91 mg, yield 99%). Yellow solid: Td 140−149 °C; 1H NMR (300 MHz, mixture of rotamers, DMSO-d6) δ = 4.10, 4.27, 4.31, 4.44, and 4.64 (5 br m, 6 H), 4.90 (s, 2 H), 7.43−7.69 (m, 5 H), 8.05 (br m, 2 H), 8.60 (br m, 1 H); 13C NMR (75 MHz, mixture of rotamers, DMSO-d6) δ = 48.4, 57.0, 57.7, 58.1, 68.1, and 68.3 (major and minor rotamers), 125.3, 129.3, 131.0, 133.1; ESI-HRMS m/z [M − NO3]+ Calcd for C13H16N7O3 318.1309, found 318.1314. Anal. Calcd for C13H16N8O6: C, 41.05; H, 4.24; N, 29.46. Found: C, 41.40; H, 4.77; N, 29.33. Catalytic Debenzylation of 1-Benzyl-1,4,6,10-tetraazaadamantan-1-ium Salts 6a, 8a, 9a and 12a. K2CO3 (34 mg, 0.25 mmol) and palladium on charcoal (10%, 15 mg) were added to a solution of N-benzyl salts 6a, 8a, 9a and 12a (0.25 mmol) in MeOH (3 mL) under argon atmosphere. The reaction vessel was evacuated and filled with hydrogen 3 times. The hydrogenation was performed at 1 atm (120 min for 6a and 9a, 105 min for 8a, 90 min for 12a). The catalyst was separated by centrifugation, and the reaction mixture was evaporated in a vacuum. Et2O or EtOAc−MeOH mixture (5:1) was added to the resulting solid, and the solution was filtered throw a short pad of Celite. The filtrate was evaporated, and the residue was dried in a vacuum (0.25 Torr) until constant weight. 4,6,10-Triacetyl-1,4,6,10-tetraazaadamantane (7a). 45 mg (yield 67%). White solid: mp 236−242 °C; 1H NMR (300 MHz, HSQC, DMSO-d6) δ = 2.09 (s, 9 H, 3 CH3), 3.18 and 3.33 (2 d, J1 = 13.5 Hz, J2 = 13.5 Hz, 6 H, 3 CH2), 6.05 (s, 3 H, 3 CH); 13C NMR (75 MHz, HSQC, DMSO-d6) δ = 20.6 (3 CH3), 54.1 (3 CH2), 57.4 (3 CH), 168.2 (CO); ESI-HRMS m/z [M + H]+ Calcd for C12H19N4O3 267.1452, found 267.1460. 4-[(tert-Butoxy)carbonyl]-1,4,6,10-tetraazaadamantane (10a). 36 mg (yield 59%). White foam: 1H NMR (300 MHz, HSQC, mixture of rotamers, DMSO-d6) δ = 1.41 (s, 9 H), 2.98 and 3.24 (2 br, 2 H), 3.01 and 3.25 (2 d, J1 = 12.6 Hz, J2 = 12.6 Hz, 4 H), 3.18 (s, 2

(CH2), 67.9 (C), 126.1 (C), 128.8 (CH), 130.3 (CH) and 133.0 (CH); ESI-HRMS m/z [M − Br]+ Calcd for C16H25N4 273.2074, found 273.2078. Anal. Calcd for C16H25BrN4 calcd: C, 54.39; H, 7.13; N, 15.86. Found: C, 54.48; H, 7.30; N, 15.58. 1,3,5,7-Tetrabenzyl-1,4,6,10-tetraazaadamantan-1-ium bromide (5c). 2.20 g (yield 76%). White solid: mp 123−130 °C (with dec.); 1H NMR (300 MHz, DMSO-d6) δ = 2.29 (s, 3 H), 2.73 (s, 6 H), 3.13 (s, 6 H), 4.54 (s, 2 H), 7.12−7.31 and 7.33−7.59 (2 m, 20 H); 13C NMR (75 MHz, DEPT, DMSO-d6) δ = 44.4 (CH2), 62.2 (CH2), 65.4 (C), 68.1 (CH2), 126.0 (C), 126.7 (CH), 127.9 (CH), 128.8 (CH), 130.3 (CH), 130.6 (CH) and 133.8 (CH), 133.0 (C); ESI-HRMS m/z [M − Br]+ Calcd for C34H37N4 501.3013, found 501.3007. 1-Methyl-1,4,6,10-tetraazaadamantan-1-ium iodide (5d). 1.27 g (yield 90%). White solid: mp 195−206 °C (with dec.); 1H NMR (300 MHz, DMSO-d6) δ = 2.90−3.40 (br s, 3 H), 3.14 (s, 3 H), 3.68 (s, 6 H), 4.24 (s, 3 H); 13C NMR (300 MHz, DMSO-d6) δ = 53.2, 59.4, 63.5; ESI-HRMS m/z [M − I]+ Calcd for C7H15N4 155.1291, found 155.1290. 1,3,5,7-Tetramethyl-1,4,6,10-tetraazaadamantan-1-ium iodide (5e). 1.49 g (yield 92%). White solid: mp = 165−202 °C (melting with dec.); 1H NMR (300 MHz, DMSO-d6) δ = 1.10 (s, 9 H), 2.25 (s, 3 H), 3.06 (s, 3 H), 3.25 (s, 6 H); 13C NMR (75 MHz, DMSO-d6) δ = 25.2, 52.7, 63.5, 65.3; ESI-HRMS m/z [M − I]+ Calcd for C10H21N4 197.1761, found 197.1782. Anal. Calcd for C10H21N4I calcd: C, 37.05; H, 6.53; N, 17.28. Found: C, 36.81; H, 6.75; N, 17.26. Catalytic Debenzylation of 1-Benzyl-1,4,6,10-tetraazaadamantan-1-ium Salts 5a−c. K2CO3 (70 mg, 0.5 mmol) and Pd/C (10%, 20 mg) were added to a solution of 5a−c (0.5 mmol) in MeOH (7.5 mL) under argon atmosphere. The reaction vessel was evacuated and filled with hydrogen, and the hydrogenation was performed for 30 min. Then the catalyst was removed by centrifugation, and the solution was evaporated in a vacuum (40 Torr) at 35 °C. Et2O was added to the resulting solid, and the solution was filtered throw a short pad of Celite. The filtrate was evaporated, and the residue was dried in a vacuum (0.25 Torr) until constant weight to give adamantanes 1a−c. 3,5,7-Trimethyl-1,4,6,10-tetraazaadamantane (1b). 73 mg (yield 80%). White foam: 1H NMR (300 MHz, DMSO-d6) δ = 0.86 (s, 9 H), 1.46 (s, 3 H), 2.66 (s, 6 H); 13C NMR (75 MHz, DEPT, DMSO-d6) δ = 27.3 (CH3), 60.6 (CH2), 63.3 (C); ESI-HRMS m/z [M + H]+ Calcd for C9H19N4 183.1604, found 183.1611. 3,5,7-Tribenzyl-1,4,6,10-tetraazaadamantane (1c). 137 mg (yield 67%). White foam: 1H NMR (300 MHz, HSQC, DMSO-d6) δ = 1.2 (br, 3 H), 2.45 (s, 6 H), 2.71 (s, 6 H), 7.06−7.25 (m, 15 H); 13C NMR (75 MHz, HSQC, DMSO-d6) δ = 45.4 (CH2), 59.6 (CH2), 64.0 (C), 126.2 (CH), 127.8 (CH) and 130.3 (CH), 135.0 (C); ESI-HRMS m/z [M + H]+ Calcd for C27H31N4 411.2543, found 411.2541. Synthesis of 4,6,10-Triacetyl-1-benzyl-1,4,6,10-tetraazaadamantan-1-ium bromide (6a). 1-Benzyl-1,4,6,10-tetraazaadamantan1-ium bromide 5a (110 mg, 0.354 mmol) was dissolved in AcOH (3 mL) and Ac2O (500 μL, 5.3 mmol) was added, and reaction mixture was kept for 20 h with occasional stirring. The volatile components were evaporated, and residue was triturated with mixture EtOAc− MeOH (10:1) and dried in a vacuum (0.25 Torr) to give 6a as white solid (142 mg, yield 92%): mp 230−235 °C; 1H NMR (300 MHz, DMSO-d6) δ = 2.14 (s, 9 H), 3.90 and 4.02 (2 br m, 6 H), 4.82 (s, 2 H), 6.68 (s, 3 H), 7.50−7.61 (m, 5 H); 13C NMR (75 MHz, DMSOd6) δ = 20.5, 56.6, 58.6, 67.5, 125.6, 129.1, 130.7, 133.0, 167.9; ESIHRMS m/z [M − Br]+ Calcd for C19H25N4O3 357.1921, found 357.1921. Synthesis of 1-Benzyl-4-[(tert-butoxy)carbonyl]-1,4,6,10-tetraazaadamantan-1-ium bromide (8a). Boc2O (665 μL, 3.21 mmol) was added to a solution of 5a (100 mg, 0.32 mmol) in MeOH (5 mL). The reaction was stirred for 3 h, and volatile components were evaporated in a vacuum. The residue was triturated with Et2O and dried in a vacuum (0.25 Torr) until constant weight (125 mg, 95%). White solid: mp 210−214 °C; 1H NMR (300 MHz, mixture of rotamers, DMSO-d6) δ = 1.42 (s, 9 H), 3.48 (s, 2 H), 3.65 (s, 2 H), 3.70 (s, 4 H), 4.22 (br s, 1 H, W = 8.5 Hz), 4.74 (s, 2 H), 5.19 (br s, W = 8.5 Hz, 2 H), 7.49−7.60 (br s, W = 3.5 Hz, 5 H); 13C NMR (75 MHz, mixture of rotamers, DMSO-d6) δ = 27.8 and 27.9 (minor and 6084

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H), 3.55 (s, 1 H), 4.64 (s, 2 H); 13C NMR (75 MHz, mixture of rotamers, HSQC, DMSO-d6) δ = 27.9 and 28.1 (C(CH3)3, minor and major rotamers), 55.4 and 55.7 (3 CH2), 59.4 (HN−CH−NH), 60.3 and 61.9 (2 br, W = 35 and 35 Hz, 2 HN−CH−NBoc), 78.8 and 79.4 (C(CH3)3), 152.7 (CO); ESI-HRMS m/z [M + H]+ Calcd for C11H21N4O2 241.1659, found 241.1652. 4,6-Diacetyl-10-[(tert-butoxy)carbonyl]-1,4,6,10-tetraazaadamantane (11a). 53 mg (yield 65%). White foam: 1H NMR (300 MHz, HSQC, mixture of rotamers, DMSO-d6) δ = 1.39 and 1.42 (2 s, 9 H, C(CH3)3), 2.07, 2.10, and 2.14 (3 s, 6 H, 2 CH3CO), 3.09−3.40 (m, 6 H, 3 CH2), 5.69, 6.01, 6.13, and 6.51 (4 s, 3 H, 3 CH); 13C NMR (75 MHz, mixture of rotamers, DEPT, HSQC, DMSO-d6) δ = 20.3 and 20.6 (2 CH3CO), 27.6 (C(CH3)3), 52.4, 53.7, 54.2, and 54.4 (3 CH2), 55.8, 57.3, and 60.4 (3 CH), 80.6 (C(CH3)3), 153.1 (O−C O), 166.3 and 168.0 (2 H3CCO); ESI-HRMS m/z [M + K]+ Calcd for C15H24N4O4K m/z 363.1429, found 363.1426. 4,6,10-Tris(3-oxobutyl)-1,4,6,10-tetraazaadamantane (13a). 56 mg (yield 64%). Colorless oil: 1H NMR (300 MHz, HSQC, DMSOd6) δ = 2.07 (s, 9 H, 3 CH3), 2.46 (m, 6 H, 3 CH2CH2COCH3), 2.94− 3.06 (m, 12 H, 3 CH2CH2COCH3 and 3 CH2 in adamantane cage), 3.26 (s, 3 H, 3 CH); 13C NMR (75 MHz, HSQC, DMSO-d6) δ = 29.7 (3 CH 3 ), 42.5 (3 CH 2 CH 2 COCH 3 ), 47.5 and 52.5 (3 CH2CH2COCH3 and 3 CH2 in adamantane cage), 68.7 (3 CH), 208.2 (3 CO); ESI-HRMS m/z [M + H]+ Calcd for C18H31N4O3 m/z 351.2391, found 351.2374.

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Weir, M. L.; Willis, A. C.; Wild, S. B.; Dilda, P. J. Organometallics 2012, 31, 1808. (f) Fokin, A. A.; Zhuk, T. S.; Pashenko, A. E.; Dral, P. O.; Guchenko, P. A.; Dahl, J. E. P.; Carlson, R. M. K.; Koso, T. V.; Serafin, M.; Schreiner, P. R. Org. Lett. 2009, 11, 3068. (g) Schreiner, P. R.; Chernish, L. V.; Gunchenko, P. A.; Tikhonchuk, E. Y.; Hausmann, H.; Serafin, M.; Schlecht, S.; Dahl, J. E. P.; Carlson, R. M. K.; Fokin, A. A. Nature 2011, 477, 308. (h) Uhl, W.; Cuypers, L.; Neumüller, B.; Weller, F. Organometallics 2002, 21, 2365. (i) Engler, E. M.; Farcasiu, M.; Sevin, A.; Cense, J. M.; Schleyer, P. v. R. J. Am. Chem. Soc. 1973, 95, 5769. (j) Fort, R. C.; Schleyer, P. v. R. J. Am. Chem. Soc. 1964, 86, 4194. (3) (a) Butlerow, A. Ann. Chem. Pharm. 1859, 111, 242. (b) Butlerow, A. Ann Chem. Pharm. 1860, 115, 322. (c) Determination of urotropine structure by X-Ray: Dickinson, R. G.; Raymond, A. L. J. Am. Chem. Soc. 1923, 45, 22. (4) (a) Eller, K.; Henkes, E.; Rossbacher, R.; Höke, H. Amines, Aliphatic. Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, 2000. (b) Seneca, H.; Peer, P. Clinical Pharmacology and Antibacterial Action of Methenamine and Its Salts; Med. Times: New York, 1969. (c) Salamone, J. S. Polymeric Material Encyclopedia; CRC Press: New York, 1996. (d) Agrawal, J. P.; Hodgson, R. D. Organic Chemistry of Explosives; John Wiley & Sons: Chichester, U.K., 2007. (e) Sheftel, V. O. Indirect Food Additivies and Polymers: Migration and Toxicology; CRC Press: Boca Raton, FL, 2000. (f) Blazevic, N.; Kobah, D.; Belin, B.; Sunjic, V.; Kaifez, F. Synthesis 1979, 161. (g) Kirillov, A. M. Coord. Chem. Rev. 2011, 255, 1603. (5) For the preliminarily communication, see: Semakin, A. N.; Sukhorukov, A. Yu.; Lesiv, A. V.; Ioffe, S. L.; Lyssenko, K. A.; Nelyubina, Yu. V.; Tartakovsky, V. A. Org. Lett. 2009, 11, 4072. (6) Ho, H.-O.; Li, W.-K. J. Serb. Chem. Soc. 2005, 70, 661. (7) Relative ΔH298 values in Scheme 1 are given for the most stable isomer of each tetraazaadamantane with respect to positions of N−H hydrogens; for relative ΔH298 values for all 14 possible structures, see Supporting Information. All calculations were performed using Gaussian 09 package. (8) For the application of adamantane scaffold in the design of functional molecules, see: (a) Grillaud, M.; Russier, J.; Bianco, A. J. Am. Chem. Soc. 2014, 136, 810. (b) Balija, A. M.; Kohman, R. E.; Zimmerman, S. C. Angew. Chem., Int. Ed. 2008, 47, 8072. (c) Kohman, R. E.; Zimmerman, S. C. Chem. Commun. 2009, 794. (d) Nasr, K.; Pannier, N.; Frangioni, J. V.; Maison, W. J. Org. Chem. 2008, 73, 1056. (e) Fleck, C.; Franzmann, E.; Claes, D.; Rickert, A.; Maison, W. Synthesis 2013, 45, 1452. (f) Peng, J.; Kishi, Y. Org. Lett. 2012, 14, 86. (g) Weidner, T.; Zharnikov, M.; Hoßbach, J.; Castner, D. G.; Siemeling, U. J. Phys. Chem. C 2010, 114, 14975. (h) Lim, H.; Chang, J. Y. Macromolecules 2010, 43, 6943. (i) Dondoni, A.; Marra, A. J. Org. Chem. 2006, 71, 7546. (j) Tolbin, A.Yu.; Sukhorukov, A. Yu.; Ioffe, S. L.; Lobach, O. A.; Nosik, D. N.; Tomilova, L. G. Mendeleev Commun. 2010, 1, 24. (9) (a) Jacobs, W. A.; Heidelberger, M. J. Biol. Chem. 1915, 20, 659. (b) Delepine, M. Bull. Soc. Chim. 1895, 13, 356. (c) Timoshenko, V. M.; Markitanov, Y. M.; Shermolovich, Y. G. Tetrahedron Lett. 2011, 52, 6619. (10) (a) Kiss, P.; Holly, S. Chem. Ber. 1981, 114, 61. (b) Lewin, G.; Bernadat, G.; Aubert, G.; Cresteil, T. Tetrahedron 2013, 69, 1622. (c) Moehrle, H.; Arndt, P. Z. Naturforsch., B: J. Chem. Sci. 2005, 688. (11) (a) Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Agents; Burke, S. D., Danheiser, R. L., Eds.; John Wiley and Sons: Chichester, 1999. (b) Almqvist, F.; Andersson, H.; Banchelin, T. S.-L.; Hussain, M.; Olsson, R. Org. Lett. 2013, 15, 54. (c) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F. Tetrahedron Lett. 1990, 31, 3351. (d) Borhade, R. G.; Gurjar, M. K.; Puranik, V. G.; Ramana, C. V. Tetrahedron Lett. 2006, 47, 6979. (12) (a) Quast, H.; Berneth, C.-P. Chem. Ber. 1983, 116, 1345. (b) Nielsen, A. T.; Christian, S. L.; Moore, D. W. J. Org. Chem. 1987, 52, 1656. (c) Mehta, G.; Vidya, R.; Sharma, P. K.; Jemmis, E. D. Tetrahedron Lett. 2000, 41, 2999. (13) Without ultrasonic activation, full conversion of starting compounds could not be reached in most cases.

ASSOCIATED CONTENT

S Supporting Information *

General experimental information, analytical data, X-ray data for 5a, Cartesian coordinates and absolute energies for all optimized geometries and NBO analysis summaries. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The support from Russian Foundation for Basic Research (Grant # 14-03-00933-a) and Russian President’s Council for Grants (Grant MK-3918.2013.3) is greatly acknowledged. Yu. V. Nelyubina thanks Russian Science Foundation (Grant # 1413-00884) for financial support of structural studies.

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REFERENCES

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(14) For application of ultrasonic activation in zinc reduction, see: Handbook on Applications of Ultrasound: Sonochemistry for Sustainability; Chen, D., Sharma, S. K., Mudhoo, A., Eds.; CRC Press: Boca Raton, FL, 2011. (15) Semakin, A. N.; Sukhorukov, A. Yu.; Nelyubina, Yu. V.; Ioffe, S. L.; Tartakovsky, V. A. Synthesis 2012, 1095. (16) Shao, M.-C.; Wang, L.-F.; Zheng, X.-V.; Tang, Y.-Q. Acta Chim. Sinica 1982, 40, 223. (17) For the effect of anomeric interactions on the bond angle, see: Pinto, B. M.; Schlegel, H. B.; Wolfe, S. Can. J. Chem. 1987, 65, 1658. (18) Sil’nikov, V. N.; Luk’yanchuk, N. P.; Shishkin, G. V. Russ. Chem. Bull. 1999, 48, 1146. (19) Semakin, A. N.; Sukhorukov, A. Yu.; Lesiv, A. V.; Khomutova, Yu. A.; Ioffe, S. L. Synthesis 2007, 2862.

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